Resveratrol, i.e, 3,4,5-trihydroxystilbene, has been intensively studied recently, in relation to the known beneficial properties of red wine, of which it is one of the fundamental ingredients (Life Sci., 71, 2145-52, 2002).
Resveratrol is located in the skins of black grapes in amounts ranging from 50 to 100 μg/gram and its concentration in red wine ranges from 1.5 to 3 mg/l.
Numerous studies have demonstrated an anticarcinogenic activity of resveratrol, the mechanisms of action of which can be subdivided as follows: inhibition of activation of transcription factor NF-kB, capable of regulating the expression of various genes involved in inflammatory and carcinogenic processes (Lancet, 341, 1103-1104, 1993; Science, 275, 218-220, 1997; Proc. Natl. Acad. Sc., 94, 14138-14143, 1997; Life Science, 61, 2103-2110, 1997; Brit. J. Pharin., 126, 673-680, 1999; J. Imm., 164, 6509-6519, 2000); inhibition of various proteins, including protein kinase C (Bioch., 38, 13244-13251, 1999), ribonucleotide reductase (FEBS Lett., 421, 277-279, 1998) and cyclo-oxygenase-2 (COX-2) in mammalian epithelial cells (Ann. N.Y. Acad. Sci, 889, 214-223, 1999; Carcinog., 21, 959-963, 2000); activation of caspases 2, 3, 6 and 9 (FASEB J., 1613-1615, 2000) and modulation of the gene p53, which is a known tumour suppressor (Cancer Research, 59, 5892-5895, 1999; Clin. Bioch., 34, 415-420, 2001).
Among the beneficial actions of resveratrol we should also mention its antioxidant activity, suggested by the above-mentioned ability to counteract the damaging effects produced by various substances and/or conditions that cause intracellular oxidative stress (Free Radic. Res., 33, 105-114, 2000).
Resveratrol can induce vascular relaxation by means of production of nitric oxide at the vascular endothelial level (Cancer Res., 59, 2596-01, 1999), inhibit the synthesis of thromboxane in platelets (Clin. Chim. Acta, 235, 207-219, 1995; Int. J. Tissue React., 17, 1-3, 1995), and of leukotrienes in neutrophils and prevent the oxidation and aggregation of low-density lipoproteins (LDL) (Lancet, 341, 1103-1104, 1993; Life Sci., 64, 2511-2521, 1999).
Recently, an inhibitory activity of resveratrol against the Herpes Simplex DNA virus has been demonstrated (Antiv. Res., 43, 145-155, 1999) on the basis of in-viutro experimental systems.
Data obtained by the present authors and by other research teams have revealed that many antioxidant substances are capable of inhibiting the replication of the parainfluenza Sendai virus (SV) type 1, of the Herpes Simplex 1 virus (HSV-1) and of the acquired immunodeficiency virus (HIV) in vitro (AIDS Res. Hum. Retoviruses, 1997: 1537-1541; Biochem. Biophys. Res. Communt., 1992; 188, 1090-1096; Antivir. Res., 1995, 27, 237.253). The antiviral efficacy of antioxidant substances has also been demonstrated in a murine AIDS (MAIDS) model, as well as in HSV1 keratitis (AIDS Res. Hum. Retroviruses, 1996: 12, 1373-1381: Exp. Eye. Res., 200: 70, 215-220).
Influenza is an epidemiological problem of worldwide proportions with serious public health problems as a result and with major health-care economic repercussions. The virus responsible for influenza is widespread and highly infectious. Unfortunately, the therapies currently available are still not fully effective and often lead to the selection of resistant viral strains (Fields, cap47, 1533-79, 2001) and, what is more, the vaccination campaigns, in addition to the disadvantages inherent in vaccine-based prevention, do not as yet provide satisfactory cover owing to the extreme antigenic variability of the virus (Fields, cap47, 1533-79, 2001).
Among the various strategies for attacking viral replication, recent studies (J. of Virol., 74, 1781-1786, 2000) have reported the important role of protein M1 in the transportation of specific virus ribonucleoproteins to the cytoplasm. This appears to be a fundamental stage in the replication cycle of the virus, so much so that inhibition of viral replication can be pursued through retention of the nucleoprotein in the nucleus of the infected cell due to the inhibited synthesis of protein M. This phenomenon may be attributable to inhibition of cell proteins with a kinase function. In fact, it has recently been demonstrated that inhibition of the kinases causes retention of the NP of the cell nucleus (Nature Cell. Biol., 3, 301-5, 2001; J. of Virol., 74, 1781-86, 2000), together with a potent inhibitory action against replication of the influenza virus.
GSH is known to be the main antioxidant in the cellular redox system and has been associated with the replication of various viruses. In fact, previous studies conducted by the present inventors have demonstrated that during viral infection it is possible to observe a reduction in GSH levels as a result of the infection itself (Rotilio et al., “Oxidative stress on cell activation in viral infection”, 143-53, 1993; Palainara et al., Antiviral Research, 27, 237-53, 1995).
Aberrant regulation of the known mechanism of apoptosis is the underlying factor responsible for numerous human diseases, such as a number of autoimmune, infectious or neurological diseases such as AIDS and cancer.
In previous studies, it has been described that resveratrol permits the elimination of tumour cells through induction of apoptosis of the cells. Recently, studies conducted by Tinhofer I. et al. (FASEB J., 18, 1613-15, 2001) have revealed that the first events of apoptosis induced by resveratrol are characterised by alteration of the mitochondrial membrane potential (ΔΦm), by the release of reactive oxygen species (ROS) and by activation of caspases 2, 3, 6 and 9. It is also known that the influenza virus induces apoptosis in various percentages, according to the viral strain and the multiplicity of infection.